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Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice
- Source :
- PAIN, PAIN, Elsevier, 2021, Publish Ahead of Print, ⟨10.1097/j.pain.0000000000002276⟩, PAIN, 2021, 162 (12), pp.2841-2853. ⟨10.1097/j.pain.0000000000002276⟩, Pain
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Supplemental Digital Content is Available in the Text. Mefloquine/amitriptyline THN101 combination reduces cuff-induced neuropathic hypersensitivity by recruiting noradrenergic descending pathways and α2 adrenoceptors and by blocking connexin in mice.<br />Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms, and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and importantly, connexins—transmembrane proteins involved in cell–cell communication—contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the antihyperalgesic effect of amitriptyline, a widely used antidepressant. In this study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. In addition, we showed that this potentiation was not due to pharmacokinetic interactions between the 2 drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenoceptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain.
- Subjects :
- Amitriptyline
[SDV]Life Sciences [q-bio]
Carbenoxolone
Antidepressive Agents, Tricyclic
Pharmacology
Neuropathic pain
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Mefloquine
business.industry
Long-term potentiation
Antidepressive Agents
Rats
3. Good health
[SDV] Life Sciences [q-bio]
Anesthesiology and Pain Medicine
Neurology
chemistry
Neuralgia
Antidepressant
Neurology (clinical)
Serotonin
business
030217 neurology & neurosurgery
Research Paper
Tricyclic
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 03043959 and 18726623
- Database :
- OpenAIRE
- Journal :
- PAIN, PAIN, Elsevier, 2021, Publish Ahead of Print, ⟨10.1097/j.pain.0000000000002276⟩, PAIN, 2021, 162 (12), pp.2841-2853. ⟨10.1097/j.pain.0000000000002276⟩, Pain
- Accession number :
- edsair.doi.dedup.....24305fc7e1fa53636f828d27fe9f0761